The impact of COVID-19 during pregnancy on maternal and neonatal outcomes: a systematic review

Several months after the onset of the epidemic, COVID-19 remains a global health issue. Scientific data on pregnancy, perinatal outcomes and vertical transmission of SARS-CoV-2 are constantly emerging but are still limited and unclear. The purpose of this systematic review was to summarize current evidence on vertical transmission rates, maternal, perinatal and neonatal outcomes and mode of delivery in pregnancies affected by COVID-19. An extensive search was conducted in PubMed, Google Scholar, Embase, and Scopus databases up to June 20, 2020. A total of 133 articles (51 case reports, 31 case series, 40 cohort studies and 2 case-control studies) reporting data from 8,092 subjects (6,046 pregnant women and 2,046 neonates) were considered eligible for inclusion in the systematic review. A substantial proportion of pregnant women with COVID-19 underwent caesarean section (case reports 82.2%, case series 74.2% and cohort studies 66.0%). Regarding vertical transmission, most neonates were tested negative (case reports 92.7%, case series studies 84.2%, cohort studies 97.1% and case control studies 100%). Maternal mortality rates ranged from 1% in cohort studies to 5.7% in case reports; neonatal mortality ranged from 2% in case reports to 3.3% in case series. Vertical transmission of SARS-CoV-2 from mother to child is rare. Careful screening of pregnant women seems important and specific guidelines with evidence-based decision algorithms for the mode of delivery in the context of a pregnancy affected by COVID-19 should be established.


Introduction
Coronavirus disease  is caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) and was first described in Wuhan, China in December of 2019 (Jin et al., 2020). COVID-19 was declared by the World Health Organization as pandemic on March 11, 2020(Ng et al., 2020 and can result in severe pneumonia, multi-organ failure and death (Hui et al., 2020). Over the last twenty years, two large epidemics of coronaviruses have been recorded, the SARS (Severe Acute Respiratory Syndrome) epidemic with a case fatality rate about 10.5% (WHO) and the MERS (Middle East Respiratory Syndrome) epidemic with a case fatality rate of 34.3% (WHO). According to the literature, the infections caused from SARS and MERS coronaviruses have been associated with serious maternal and neonatal morbidity and mortality, stillbirth and high percentage of spontaneous abortion (Schwartz and Graham, 2020;Wong et al., 2004). The epidemiological data from China about COVID-19 have shown that most cases had mild symptoms with a case fatality rate about 2.3%. SARS-CoV-2 seems to be more contagious on close contacts (Wu and McGoogan, 2019), albeit less aggressive than the aforementioned two coronaviruses.
Pregnancy is considered a state of relative immunological suppression, with a reduction in cellular immunity and potential susceptibility to infections (Birkeland and Kristoffersen, 1980; Goodnight and Soper, 2005); changes in hormonal levels, such as beta human chorionic gonadotropin (β-hCG), progesterone and cortisol may mediate pregnancy-related cellular immunity immunosuppression. Additionally, the increase in uterine size causes the diaphragm to rise by 4 cm, enlarging the transverse diameter of the chest by 2 cm and affecting pulmonary volume. On the other hand, the immaturity of the immune system of fetuses and neonates makes them more vulnerable to infections (van Well et al., 2017). Therefore, pregnant women and neonates could be considered a high-risk group for infection during the present pandemic.
Scientific data on pregnancy, perinatal outcomes and vertical transmission of SARS-CoV-2 are rather limited but rapidly accumulating. Over the past months, case reports and cohort studies have reported variable results on the mode of delivery, perinatal outcomes, vertical transmission from mother to infant or intrauterine transmission, and treatment modalities (Lang and Zhao, 2020;Martinelli et al., 2020;Ahmed et al., 2020;Liu W et al., 2020). The purpose of this systematic review was to summarize current evidence on vertical transmission rates, maternal, perinatal and neonatal outcomes and mode of delivery in pregnancies affected by COVID-19.

Study design
The present systematic review was performed according to the PRISMA guidelines (Liberati et al., 2009). A search was performed in PubMed, Google Scholar, Embase, and Scopus databases up to June 20, 2020. The following search terms were used: (Covid-19 OR COVID-19 OR SARS-CoV-2 OR "2019-nCoV" OR "novel coronavirus") AND (gestation OR pregnancy OR pregnant OR gestational OR neonate OR neonatal). Additionally, references of all articles were checked thoroughly.
Inclusion criteria-Only original research articles (cohort studies, cross-sectional studies, case-control studies, case series and case reports) published in the English language were included. Studies referring to pregnancies and/or deliveries of all ages with maternal confirmed COVID-19, with reverse transcription polymerase chain reaction (RT-PCR) and/or positive computed tomography (CT) findings, were deemed eligible. No limitations, such as ethnicity or journal, were considered. Studies with overlapping populations were excluded.

Eligibility assessment and risk of bias assessment
The retrieved studies were screened by three reviewers independently (D.M., A.S. and E.P.). The Newcastle-Ottawa Quality Scale (Ottawa Hospital Research Institute) was used to evaluate the quality of the studies. If there was a disagreement, team consensus followed.

Data extraction
Three authors (D.M, A.S. and E.P.) extracted all relevant data. General information, such as first author's name, location or country, study design, study period, number of participants (pregnancies or neonates), maternal age, gestational age, mode of delivery, treatment, comorbidity of the mother, maternal and neonatal outcomes and test for COVID-19 were recorded. Data were tabulated; frequencies and percentages for categorical variables were estimated.

Selection of studies
After search in the databases, a total of 666 articles were retrieved. The flow chart describing the selection of studies is presented in Figure 1.
After removal of duplicates, 354 items were selected for extensive review. Out of them, 162 articles were excluded as irrelevant to the topic and 42 articles as reviews (15 systematic reviews and 27 reviews). The remaining 150 full-text articles were subjected to further consideration; of them, 17 articles were excluded because of language (eleven in Chinese, four in French, and two in Spanish). Finally, 133 articles were included in the systematic review (Wang S et al.,  , 2020) identified 52 pregnant women (mean ± SD; age 29.7 ± 9.1 years; gestational age 33.1 ± 6.3 weeks) from January 2020 to May 2020. The characteristics of case reports are summarized in Table 1 in Supplementary Data 1 . The cases derived mostly from China (n=15), with US being the second most frequent location (n=11), followed by Italy, UK, Iran, Jordan, and Turkey (n=3), while Korea, Honduras, Sweden, Peru, Australia, Thailand, Spain, Switzerland, Portugal, Belgium, contributed one case each. All women presented to the emergency room for respiratory complications. Among them, 29 women had co-morbid health conditions, i.e. gestational diabetes (n=9), obesity (n=9), hypothyroidism (n=5), hypertension (n=3), asthma (n=2), thalassemia (n=1), myotonic dystrophy (n=1), pneumonia (n=1), respiratory failure (n=1), HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome (n=1), hepatitis B (n=1), thyroidectomy (n=1), immune thrombocytopenia (ITP) (n=1) and cholecystitis (n=1). All 52 pregnant women had COVID-19, confirmed either through RT-PCR or RT-PCR and CT scans.

Case series
Demographics in case series: From the 31 case series, 16 derived from China, 5 from New York City, 2 from Italy, 2 from the UK, 2 from New Jersey, and 1 from Canada, Iran, Portugal and Turkey, respectively, as presented in Table 2 Table 2 in Supplementary Data 1 ).

Cohort Studies
Demographics in cohort studies: The 40 cohort studies identified 5,242 pregnant women, from which 2,685 (51% 2,685/5,242) were confirmed cases of COVID-19 through RT-PCR or CT scan ( Table 3 in Supplementary Data 1 ) and were included in the present study (Chen et Table 3 Table 3 in Supplementary Data 1 ).

Case-control studies
Two case-control studies were identified Tekbali et al., 2020). One study in New York City, in March 2020, compared 3,064 pregnant with 18,916 non-pregnant control women concerning COVID-19-related admission to hospitals. The rates of admission of pregnant/postpartum and control women increased from week 1 to week 4 of the COVID-19 outbreak from 0.14% to 5.65% and from 1.21% to 56.79%, respectively ( Table 4 in Supplementary Data 1 ).

Risk of bias:
According to Newcastle-Ottawa scale ratings the majority of the 40 cohort studies were identified as good or fair quality studies (11/40 and 17/40, respectively). Eleven studies were scored as poor quality (Breslin et  . Short follow-up period was the most prominent factor compromising the quality of studies. Most studies presented clear inclusion criteria, with detailed description of the sample (pregnant women exposed to SARS-CoV-2, randomly selected) while data were derived from reliable, hospital records. Unadjusted (univariate) estimates were provided as a rule; almost half of the studies included a non-exposed group that matched with the exposed group in factors, such as age, gestational age, delivery mode and comorbidities. In the studies of poor quality, there was no description of the non-exposed group or any comparison with the exposed one.

Discussion
COVID-19 is a global health issue, several months after the onset of the outbreak. Pregnant women are considered a high risk group, not only physically, but psychologically as well (Birkeland and Kristoffersen, 1980 . In cases where the neonates were tested positive, the virus might have been transmitted in other ways, such as with touch, droplets or breast milk ; therefore, the value of universal screening of women admitted for delivery has been supported, especially because many positive women are asymptomatic. Thus, it is of paramount importance to screen pregnant women before labor Fassett et al., 2020).
Caesarean section has been the most common mode of delivery since the start of the COVID-19 epidemic and especially in China, with a rate over 90% . A previous systematic review reported that about 75% of the infected women delivered by C-section (Corbett et al., 2020). According to the present systematic review, a substantial proportion of pregnant women with COVID-19 underwent C-section (case reports 82.2%, case series 74.2% and cohort studies 66.0%). Recent guidelines suggest C-section to be considered in cases of severe and critical infections while taking into account possible risks (Royal College of Obstetricians and Gynecologists, 2020). On the other hand, a study from Spain reported that deliveries by C-section were significantly associated with clinical deterioration of positive mothers (Martínez-Perez et al., 2020). Additionally, there is no evidence that the rate of neonatal COVID-19 is lower when the baby is born by C-section , hence, C-section could be applied in cases where other indications also exist (Ashokka et al., 2020).
In many studies the reason for C-section was not mentioned. It is possible that, because COVID-19 complications are not well-known, especially in the vulnerable group of pregnant women and neonates, increased anxiety of both mothers and doctors might have led to rash decisions. Actually, as already mentioned, C-section was the rule in China and other countries during the first months of the pandemic (Martínez-Perez et al., 2020).
According to Zaigham and Andersson (Zaigham and Andersson, 2020), COVID-19 is a risk factor for increased maternal and perinatal morbidity, probably due to higher rates of preterm birth in mothers with COVID-19 (Allotey et al., 2020). Two maternal deaths and only one neonatal death were reported in a recent systematic review, including 324 pregnant women . Our study comprised a larger sample with mortality rates ranging from 1% in cohort studies to 5.7% in case reports in mothers, and from 2% in case reports to 3.3 % in case series in neonates. Further studies are needed to estimate standardized mortality ratios in COVID-19 pregnant women and their neonates versus pregnant control women, addressing the confounding effects of comorbidities, as pre-existing comorbidities of the mother such as advanced maternal age and high body mass index are potential risk factors for severe COVID-19 during pregnancy (Allotey et al., 2020).
The main limitation of the present systematic review is that most of the currently available studies did not provide detailed data for participants, probably due to the emergency nature of the subject. Additionally, a substantial amount of evidence was derived from case reports and case series. Moreover, the inadequacy of follow-up periods reduced the validity of cohort studies. Finally, the lack of important data in many studies, such as the positivity of neonates in SARS-CoV-2 testing, mode of delivery and indication for C-section, did not allow extensive analyses.
On the other hand, this systematic review has several strengths as it includes a large sample with detailed data about the mode of labour, morbidity, and vertical transmission. Case reports and case series highlighted important aspects of the disease. Moreover, studies from all continents, except Africa, were included, whereas existing systematic reviews refer mostly to studies derived from China.
In conclusion, according to the present systematic review, vertical transmission of COVID-19 from mother to child is rare. Nevertheless, careful screening of pregnant women seems important in view of adverse health outcomes for the mother and the neonate. Specific guidelines with evidence-based decision algorithms for the mode of delivery in the context of a pregnancy affected by COVID-19 are needed.

Supplementary Material
Refer to Web version on PubMed Central for supplementary material.

Funding sources
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Author Manuscript